The present invention relates to methods for moving a manipulation and/or examination device, particularly a probe, through biological cell material which is formed from biological cells, manipulation and/or examination devices which are adapted for performing methods of this type, cell manipulators which have at least one manipulation and/or examination device of this type, and applications of the cited methods.
In medicine, biotechnology, and biochemistry, there are numerous methods in which biological cells are examined or processed or used for examining or processing biological materials. For example, for medicinal cell therapy, cells are taken from an animal or human subject, treated, collected, sorted, and/or cultivated outside the subject body, in order to subsequently return specific cells or cell groups into the subject. Special advantages are expected from medicinal cell therapy using stem cells, since these have the capability of differentiation into nearly all cell types of the body and therefore represent candidates for individual cell therapies and for in vitro regeneration of tissue. It is currently assumed that adult or embryonic stem cells are capable, under suitable conditions, of nearly all cell performances of the body and therefore also for producing or regenerating different tissues. There is a strong interest in safe and reproducible handling of biological cells.
The essential objects in the examination or manipulation of biological cells, particularly in connection with medicinal cell therapy and tissue engineering, are that at predefined locations, for example, in the tissue or in a cell composite, individual, previously selectable cells or cell groups are to be able to be inserted or removed or defined measurements are to be able to be performed with a precision in the μm range. These objects must be able to be achieved with high reproducibility, controllability, and precision without impairing or damaging the cells or the tissue. Until now, these requirements have not been satisfactorily fulfilled. For example, in animal experiments, in spite of identically performed methods, e.g., for the injection of cells into diseased tissue, contradictory results have been achieved. It has been determined that the positive course of a tissue regeneration is sensitively dependent on the method conditions, particularly on the type of the injection, the number of cells or substances introduced, and the injection tools used. In numerous experiments known from practice, the desired regeneration or new formation of a cell or tissue type did not occur, but rather an induction of tumors, for example. It is assumed that the induction of tumors as the uncontrolled cell reproduction of stem cells is encouraged through physical, chemical, or mechanical external influences at the injection location. These influences may not be reproducibly set or at least detected using the conventional injection technologies.
Until now, cannulas or hypodermic needles have been used as the injection tools. For example, FIG. 9 shows the tip of a conventional injection cannula 10′ in an enlarged side view. The injection cannula 10′ has a hollow cannula body 11′, whose free end 12′ is beveled and possibly ground to form a tip. In order to form the straightest and most reproducible injection channel possible into a tissue, the cannula body 11′ is implemented as thin as possible and the end 12′ is implemented as pointed and sharp. Although the conventional injection cannula 10′ for precision applications has an extremely small diameter in the submillimeter range and the end 12′ runs to a sub-μm tip, injury-free insertion into a tissue is basically excluded in the conventional application of the cannula. As soon as the tip hits cells at the high injection velocity currently used in a tissue, these are mechanically injured, crushed or torn, for example.
Performing subcutaneous endoscopy by inserting endoscopes or auxiliary devices into subcutaneous tissue is generally known from medical technology. However, subcutaneous endoscopy is always connected with injury to tissue and blood vessels and is therefore unsuitable for the biotechnological processing of cell materials.
The problems cited in cell therapy and the currently partially unsatisfactory results in tissue engineering currently represent the most important restrictions and delays of a broad application of these methods in biotechnology and medicine.
The object of the present invention is to provide improved methods for moving a foreign body, particularly a manipulation and/or examination device (or probe) through a cell material which is formed from biological cells, using which the problems of the conventional injection methods are countered and which are suitable in principle for fulfilling the requirements listed above in cell technologies. It is particularly the object of the present invention to provide improved methods for inserting a manipulation and/or examination device into cell tissue or cell groups, using which cells or other substances are insertable into the cell material, cells or cell components are removable from the cell material, and/or measurements are performable in the cell material. It is also the object of the invention to provide improved manipulation and/or examination devices for performing methods of this type and injection devices equipped with at least one device of this type, using which the disadvantages of conventional injection tools are overcome. A further object of the present invention is to specify novel applications of the insertion of probes into cell material.